In the phage-only study, the PEV31 titer gradually decreased in the lungs over 24?h, with a half-life of approximately 8 h for both doses. In the presence of bacteria, in contrast, the PEV31 titer increased by almost 2-log10 in the lungs at 16 h. Furthermore, bacterial growth was suppressed in the PEV31-treated group, while the PBS-treated group showed exponential growth. Of the 10 colonies tested, four phage-resistant isolates were observed from the lung homogenates sampled at 24 h after phage treatment. These colonies had a different antibiogram to the parent bacteria. This study provides evidence that pulmonary delivery of phage PEV31 in mice can reduce the MDR bacterial burden.For a long while, 8-aminoquinoline compounds have been the only therapeutic agents against latent hepatic malaria parasites. These have poor activity against the blood-stage plasmodia causing acute malaria and must be used in conjunction with partner blood schizontocidal agents. We examined the impacts of one such agent, chloroquine, upon the activity of primaquine, an 8-aminoquinoline, against hepatic stages of Plasmodium cynomolgi, Plasmodium yoelii, Plasmodium berghei, and Plasmodium falciparum within several ex vivo systems-primary hepatocytes of Macaca fascicularis, primary human hepatocytes, and stably transformed human hepatocarcinoma cell line HepG2. Primaquine exposures to formed hepatic schizonts and hypnozoites of P. cynomolgi in primary simian hepatocytes exhibited similar 50% inhibitory concentration (IC50) values near 0.4?μM, whereas chloroquine in the same system exhibited no inhibitory activities. Combining chloroquine and primaquine in this system decreased the observed primaquine IC50 for all parasite forms in a chloroquine dose-dependent manner by an average of 18-fold. Chloroquine also decreased the primaquine IC50 against hepatic P. falciparum in primary human hepatocytes, P. berghei in simian primary hepatocytes, and P. yoelii in primary human hepatocytes. Chloroquine had no impact on primaquine IC50 against P. yoelii in HepG2 cells and, likewise, had no impact on the IC50 of atovaquone (hepatic schizontocide) against P. falciparum in human hepatocytes. We describe important sources of variability in the potentiation of primaquine activity by chloroquine in these systems. Chloroquine potentiated primaquine activity against hepatic forms of several plasmodia. We conclude that chloroquine specifically potentiated 8-aminoquinoline activities against active and dormant hepatic-stage plasmodia in normal primary hepatocytes but not in a hepatocarcinoma cell line.The aim of this study was to describe the pharmacokinetics of ceftolozane-tazobactam in plasma and cerebrospinal fluid (CSF) of infected critically ill patients. In a prospective observational study, critically ill patients (?18?years) with an indwelling external ventricular drain received a single intravenous dose of 3.0 g ceftolozane-tazobactam. Serial plasma and CSF samples were collected for measurement of unbound ceftolozane and tazobactam concentration by liquid chromatography. Unbound concentration-time data were modeled in R using Pmetrics. Dosing simulations were performed using the final model. A three-compartment model adequately described the data from 10 patients. For ceftolozane, the median (interquartile range [IQR]) area under the unbound concentration-time curve from time zero to infinity (fAUC0-inf) in the CSF and plasma were 30 (19 to 128) h?mg/liter and 323 (183 to 414) h?mg/liter, respectively. For tazobactam, these values were 5.6 (2 to 24) h?mg/liter and 52 (36 to 80) h?mg/liter, respectively. Mean ± standard deviation (SD) CSF penetration ratios were 0.2?±?0.2 and 0.2?±?0.26 for ceftolozane and tazobactam, respectively. With the regimen of 3.0 g every 8 h, a probability of target attainment (PTA) of ?0.9 for 40% fT&gt;MIC in the CSF was possible only when MICs were ?0.25?mg/liter. The CSF cumulative fractional response for Pseudomonas aeruginosa-susceptible MIC distribution was 73%. The tazobactam PTA for the minimal suggested exposure of 20% fT&gt;1 mg/liter was 12%. The current maximal dose of ceftolozane-tazobactam (3.0 g every 8 h) does not provide adequate CSF exposure for treatment of Gram-negative meningitis or ventriculitis unless the MIC for the causative pathogen is very low (?0.25?mg/liter).Mutations in ERG11 were detected by gene sequencing and amino acid alignment in 18 Candida tropicalis strains with different degrees of sensitivity to voriconazole (VRC). ERG11 expression, sterol content, and membrane permeability were also evaluated. We report three missense mutations in ERG11 that resulted in resistance to VRC. The transcriptional levels of ERG11 as well as the ergosterol content and membrane permeability demonstrated no correlation to only a slight correlation with the obtained MIC values, but the data did suggest a tendency toward such a correlation.Isavuconazole is the newest triazole antifungal, and it displays a favorable pharmacokinetic and safety profile. Less is known about its long-term use in immunocompetent hosts. We performed a retrospective service evaluation of isavuconazole therapeutic drug monitoring in patients with chronic pulmonary aspergillosis. Adverse events (AEs) and dose adjustments made during routine clinical practice were recorded, and AEs were classified based on Common Terminology Criteria for Adverse Events v5.0. Forty-five patients (mean age, 64?years) had 285 isavuconazole blood drug levels measured (mean level, 4.1?mg/liter). A total of 117 measurements (41%) were performed on patients on a 100-mg daily dose instead of 200?mg, and all had blood levels of &gt;1?mg/liter. Age (P?=?0.012) and a daily dose of 200?mg versus 100?mg (P?=?0.02) were independent predictors of levels of &gt;6?mg/liter. https://www.selleckchem.com/products/cpi-0610.html AEs were recorded for 25 patients (56%). The mean drug level at the first measurement was 5.5?±?2?mg/liter for patients reporting AEs, compared with 4.2?±?1.7?mg/liter for those not reporting AEs (P?=?0.032). The cutoff threshold best predictive of an AE was 4.6?mg/liter (area under the concentration-time curve,?0.710). Sixteen patients (36%) discontinued isavuconazole therapy due to AEs. Twenty-six patients (58%) continued on isavuconazole beyond 6 months. Asthma (P?=?0.022) and a daily dose of 200?mg versus 100?mg (P?=?0.048) were associated with AEs of grade 2 or higher. A reduced daily dose (100?mg versus 200?mg) of isavuconazole resulted in satisfactory drug levels in a substantial number of patients; it was better tolerated and enabled continuation of therapy for prolonged periods.